A sizeable problem

Obesity is a serious threat to global health and a growing healthcare burden

The prevalence of obesity has grown alarmingly during the past two decades, and it is now widely accepted as one of the most serious global health threats.

According to the World Health Organisation (WHO), there are now one billion overweight adults globally, at least 300 million of whom are obese. In Europe, over 130 million people are now obese, 10–20 per cent of men and 15–20 per cent of women. WHO estimates that 150 million adults and 15 million children will be obese by 2010.

Research conducted by Mintel in 2009 shows that, in the UK alone, obesity levels are projected to increase to one-third of the population by 2010 and to over 50 per cent of the population by 2050. Associated costs to the UK economy are predicted to rise to about £22bn a year by 2015.

The WHO figures also indicate that the annual rate of increase in the prevalence of obesity among children is heading upwards too. Currently, 20 per cent of children and adolescents in Europe are overweight and one-third of this group are obese – 10 times the rate in the 1970s.

Numerous medical conditions are strongly associated with obesity – including cardiovascular disease, type 2 diabetes, end-stage renal disease, various types of cancer and osteoarthritis. A study by the Nutrition Society shows that in Europe the direct healthcare costs of obesity account for 2 to 4 per cent of national health expenditure.

Obesity market sales across the US, Japan, France, Germany, Italy, Spain and the UK were valued at $618.4m in 2007, according to Datamonitor. However, the business information group forecasts that the obesity market will slump to about $300m by 2012, before new market launches revive it to an estimated $560m by 2018.

Currently Xenical (orlistat) and Reductil (sibutramine) dominate. In 2008, Xenical accounted for 51.9 per cent of the market share in France, Germany, Italy, Spain and the UK and Reductil accounted for 23.8 per cent. In March 2009, Xenical held 76 per cent of the prescription-only anti-obesity pharmaceuticals market in the UK, according to the manufacturer, Roche.

AcompliaThe other main player in 2008 was the cannabinoid-1 receptor antagonist Acomplia (rimonabant) made by sanofi-aventis, which accounted for 24.1 per cent of market share. Concerns about psychiatric side effects and weight regain after treatment had ceased, led to the withdrawal of the drug at the end of 2008.

This has certainly left a hole in the anti-obesity market. This drug had seemed like a promising new alternative when it was authorised in 2006, but the European Medicines Agency (EMEA) recommended suspension of its marketing authorisation after concluding that the benefits of Acomplia no longer outweigh its risks. The EMEA said that data from post-marketing experience and ongoing clinical trials indicated that serious psychiatric disorders may be more common than in the clinical trials used in the initial assessment of the medicine.

Although its withdrawal was a surprise to some, anti-obesity treatments have a history of safety concerns. "Going back to the 1950s, we've had serial withdrawals of anti-obesity products for a range of reasons," says Jonathan Angell, senior analyst at Datamonitor Healthcare. "The withdrawal of rimonabant has re-ignited the efficacy-versus-safety discussion, and it will have a knock-on effect for other products in the pipeline."

XenicalThe clear market leader is Roche's Xenical. The drug selectively inhibits gastrointestinal (GI) lipases in the gut, thereby preventing absorption of around 30 per cent of ingested fat which just passes through the digestive system. Absorption of carbohydrates and proteins is not affected, but as the drug can reduce the absorption of some fat-soluble vitamins and beta-carotene, usually supplements are recommended.

Clinical trials have shown that patients treated with Xenical lose significantly more weight than placebo groups and sustain weight loss over a two-year period, with the additional advantages of improved lipid profile, blood pressure and quality of life.It is argued that one of the advantages of this treatment is that it encourages patients to reduce fat and calorie intake in their diets. When patients eat high-fat foods, gastrointestinal side effects are more likely to occur. These can include faecal urgency, faecal incontinence and leakage. Patients are advised to follow a reduced-calorie diet consisting of no more than 30 per cent of calories from fat. This may lead to obese patients making behavioural changes which could result in longer-term weight reduction. However, these side effects can be quite severe, causing significant distress.

AlliEarlier this year, controversy surrounded the launch of the OTC lower-dose formulation of orlistat (60mg), for use in adults with a body mass index (BMI) of 28 or more. Alli is the first non-prescription weight loss aid to receive a licence in the EU. Questions were asked about whether pharmacists are the best healthcare professionals to assess these patients and give them appropriate ongoing guidance. Concerns were raised about those with no medical reason for losing weight obtaining the drug and about the consumer perception that obesity can be 'cured' by simply taking a pill.

GlaxoSmithKline (GSK), (which acquired the OTC rights to the drug from Roche in 2004), has consistently denied that Alli is promoted as a 'magic pill' and stresses that users must be committed to weight loss. The company has also highlighted the strength of its comprehensive pharmacy training programme, which consists of interactive workshops and online distance learning. "GSK strongly believes pharmacists, as healthcare professionals in the local community, are ideally placed to provide customers with appropriate weight loss advice," said a company spokesperson. "It is the responsibility of the pharmacy to sell the product in line with the terms of the licence. The pharmacy therefore needs to make an assessment of a person's age and BMI before selling Alli."

The company announced European sales of Alli for Q2 2009 of £56m (solely ex-factory sales).

Most recently, The US Food and Drug Administration (FDA) announced that it will investigate patient alerts linking orlistat to hepatoxicity. GSK asserts that there is no evidence that Alli causes liver damage. "The inclusion of an adverse event onto their DAART (Document Archiving Reporting and Regulatory Tracking System) list does not mean that FDA has concluded that a risk or causal relationship exists," GSK reports. "Orlistat is the most-studied weight loss medicine, with safety established through 100 clinical studies involving more than 30,000 patients."

ReductilReductil is a satiety enhancer; the neurotransmitter reuptake inhibitor reduces the re-uptake of serotonin, norepinephrine and dopamine, thereby increasing the levels of these neurotransmitters in the brain. The drug also has established efficacy in weight reduction and maintenance of weight loss. It is manufactured by Knoll (now part of Abbott Laboratories).

Other available therapiesOther brands currently available in certain countries within Europe include the serotonin and noradrenaline reuptake inhibitor (SNRI) Ectiva, the appetite suppressants phentermine (branded as Ionamin) and antiadipositum (branded as Norpseudoephedrine, Fauspond, Exponcit N, Vita-Schlanktropfen Schuck and Mirapront-N). More controversial is the amphetamine derivative phenylpropanolamin (branded as Recatol and Boxogetten). All together these drugs make up only a tiny percentage of the market.

Therapies in the pipelineAccording to Datamonitor, there are currently four main phase III anti-obesity therapies predicted to launch within the next few years:• Contrave (bupropion and naltrexone) manufactured by Orexigen Therapeutics is estimated to launch in the US in August 2010• Qnexa (phentermine and topiramate) manufactured by Vivus and scheduled to launch in the US in April 2012• Cetilistat, with a mode of action similar to that of Xenical, is manufactured by Alizyme plc and due to launch in Japan in June 2012 • Lorcaserin, a serotonin receptor agonist from Arena Pharmaceuticals, is scheduled for launch in the US in 2011.

Contrave In July, Orexigen announced that three late-stage trials of Contrave had met their goals. The studies, involving about 3,800 patients, showed that the drug was effective at higher and lower doses compared with placebo, achieving at least 5 per cent weight loss.

Qnexa Vivus' drug has also achieved encouraging trial results. Results of the phase III EQUATE trial – presented at the 7th Annual European Congress on Obesity, in June, showed patients taking full-dose and mid-dose Qnexa achieved an average weight loss of 9.2 per cent and 8.5 per cent, respectively, as compared to 1.7 per cent reported for the placebo group.

Certilistat Alizyme, which developed Certilistat, entered administration at the end of July. It had sold the rights to develop, manufacture and market Cetilistat in Japan to Takeda Pharmaceutical in 2003. The drug acts peripherally to reduce the appetite and has been shown to produce a clinically and statistically significant weight loss in obese patients in the short term.

Jonathan Angell comments: "There have been some aggressive forecasts for pipeline products. For example, press reports have said that Contrave is predicted to achieve at least $500m in annual revenue, Lorcaserin could become a bestseller in the history of medicine and Qnexa has blockbuster potential. However, although obese or severely overweight individuals in Western society represent a massive population, the regulatory bodies are increasingly cautious and many large players have now backed away from obesity."

LorcaserinEarlier this year, Arena announced that the first of two pivotal trials for Lorcaserin demonstrated the safety and efficacy of the drug. Treatment was associated with a statistically significant categorical and average weight loss from baseline after 12 months; 47.5 per cent of Lorcaserin patients lost greater than, or equal to, 5 per cent of their body weight compared to 20.3 per cent in the placebo group.

Research and managementOver recent years a number of different genes have been associated with obesity. Studies will continue to aid scientific understanding and hopefully lead to clinical advances.

Interest in adenovirus-36 (ad-36) – which commonly causes respiratory and eye infections – continues. Researchers have shown that obese people are much more likely to have been infected with ad-36 than slim people, and even exposure to the virus has caused adult human stem cells to turn into fat-storing cells.

Datamonitor envisages that companies in the anti-obesity market will have to fight for approval, commercial support and for doctors to prescribe their products. Ultimately, the focus will need to shift from acute weight loss solutions to long-term sustainable weight management. In the meantime, surgery remains an option for the very obese.

The AuthorNicola O'Connell is a freelance healthcare writer.To comment on this article, email pme@pmlive.com